Cell-based phenotypic screening is increasingly being used for discovery of bioactive drug candidates. The targets of drug candidates naturally operate within a cellular context, and how they interact with bioactive molecules (e.g., synthetic molecules) is significantly influenced by this context. For this reason, when trying to identify unknown targets to bioactive molecules, it is preferable to allow the target to bind to the bioactive molecules within a living cell, before being captured for identification. Thus, methods that allow binding to occur in cell lysates before capture are not as preferred. This is true for the primary targets that mediate the desired bioactivity, and for off targets that may result in liabilities or interferences. Discovering and validating protein targets for such bioactive molecules often uses a combination of affinity enrichment and mass spectrometry methods. Such methods face several challenges. First, the often moderate to weak binding between a target molecule and a protein target makes it hard to capture a target protein or protein complexes or biases the results towards high affinity interactors. Moreover, affinity enrichment methods typically use a solid support immobilized with the candidate target molecule. The kinetics of binding on solid surfaces are much slower when compared to solution-based kinetics, further decreasing the chance of capturing a target protein or protein complexes. Non-specific binding of proteins from cell lysate to the solid support results in high background that further complicates the identification of the cellular target using mass spectrometry (MS). Such methods often result in a large number of putative hits, making it necessary to run secondary screens to validate the potential targets. High-throughput validation assays for target molecule-protein interactions require further development and optimization making it resource intensive process.